The purpose of this project is to define the molecular pathways of ischemic adaptation in hypertrophied myocardium. Using an isolated heart preparation, this project will examine the central hypothesis that the ischemic tolerance of hypertrophied myocardium is mediated by the cardiac renin-angiotensin system. This pathway becomes up-regulated as ventricular remodeling transitions from compensated hypertrophy to cardiac failure with a resultant decline in mechanical performance. The Specific Aims described below are formulated to test the central hypothesis of this proposal: Specific Aim 1: To characterize the effect of preconditioning on recovery of cardiac function after ischemia and reperfusion in hypertrophied and failing hearts. a. Is preconditioning enhanced in a model of pressure overload hypertrophy? b. Is the enhancement of preconditioning still preserved in the same model of pressure overload hypertrophy as the animals. transition to heart failure? Specific Aim 2: To define the role of the AT-1 receptor in cardiac preconditioning in hypertrophied and failing myocardium. a. Does inhibition or stimulation of the AT-1 signal affect MAPKinase and PKC activation in normal, hypertrophied and failing hearts? b. Does targeted inhibition of the AT-1 receptor prevent the transition from compensated hypertrophy to failure in a model of pressure overload? Specific Aim 3: To determine if AT-1 signaling is necessary and sufficient to confer cardiac preconditioning. a. Is preconditioning enhanced in AT-1 knock-out (AT-1aKO) mice? b. Is preconditioning effective in pressure-overloaded hearts from AT-1aKO mice? It is anticipated that these new mechanistic insights will advance our understanding of ischemia/ reperfusion injury and begin to identify therapeutic targets that may improve myocardial function following ischemic injury in the hypertrophied heart.